Benzothiazole derivatives

ABSTRACT

Provided are compounds and their pharmaceutically acceptable salts that are useful for the treatment of diseases related to the adenosine receptor. Also included are methods of treating patients suffering from or susceptible to at least one symptom of abuse of, dependence on, or withdrawal from at least one substance.

FIELD OF INVENTION

The present invention is related to benzothiazole compounds, and moreparticularly to benzothiazole derivatives showing activity as adenosinereceptor ligands.

BACKGROUND

Adenosine modulates a wide range of physiological functions byinteracting with specific cell surface receptors. The potential ofadenosine receptors as drug targets was first reviewed in 1982.Adenosine is related both structurally and metabolically to thebioactive nucleotides adenosine triphosphate (ATP), adenosinediphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosinemonophosphate (cAMP); to the biochemical methylating agentS-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FADand coenzyme A; and to RNA. Together adenosine and these relatedcompounds are important in the regulation of many aspects of cellularmetabolism and in the modulation of different central nervous systemactivities.

The receptors for adenosine have been classified as A₁, A_(2A), A_(2B)and A₃ receptors, belonging to the family of G protein-coupledreceptors. Activation of adenosine receptors by adenosine initiatessignal transduction mechanism. These mechanisms are dependent on thereceptor associated G protein. Each of the adenosine receptor subtypeshas been classically characterised by the adenylate cyclase effectorsystem, which utilises cAMP as a second messenger. The A₁ and A₃receptors, coupled with G_(i) proteins inhibit adenylate cyclase,leading to a decrease in cellular cAMP levels, while A_(2A) and A_(2B)receptors couple to G_(s) proteins and activate adenylate cyclase,leading to an increase in cellular cAMP levels. It is known that the A₁receptor system include the activation of phospholipase C and modulationof both potassium and calcium ion channels. The A₃ subtype, in additionto its association with adenylate cyclase, also stimulates phospholipaseC and so activates calcium ion channels.

The A₁ receptor (326-328 amino acids) was cloned from various species(canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95%sequence identity among the mammalian species. The A_(2A) receptor(409-412 amino acids) was cloned from canine, rat, human, guinea pig andmouse, with a 93% homology of A_(2A) receptor clone isolated from thehuman hippocampal library and from the dog. The A_(2B) receptor (332amino acids) was cloned from human and mouse with 45% homology of humanA_(2B) with human A₁ and A_(2A) receptors. The A₃ receptor (317-320amino acids) was cloned from human, rat, dog, rabbit and sheep.

The A₁ and A_(2A) receptor subtypes are proposed to play complementaryroles in adenosine's regulation of the energy supply. Adenosine, whichis a metabolic product of ATP, diffuses from the cell and acts locallyto activate adenosine receptors to decrease the oxygen demand (A₁) orincrease the oxygen supply (A_(2A)) and so reinstate the balance ofenergy supply: demand within the tissue. The actions of both subtypesare to increase the amount of available oxygen to tissue and to protectcells against damage caused by a short term imbalance of oxygen. One ofthe important functions of endogenous adenosine is preventing damageduring traumas such as hypoxia, ischaemia, hypotension and seizureactivity.

Furthermore, it is known that the binding of the adenosine receptoragonist to mast cells expressing the rat A₃ receptor resulted inincreased inositol triphosphate and intracellular calciumconcentrations, which potentiated antigen induced secretion ofinflammatory mediators. Therefore, the A₃ receptor plays a role inmediating asthmatic attacks and other allergic responses.

Adenosine is also a neuromodulator, possessing global importance in themodulation of molecular mechanisms underlying many aspects ofphysiological brain function by mediating central inhibitory effects. Anincrease in neurotransmitter release follows traumas such as hypoxia,ischaemia and seizures. These neurotransmiters are ultimatelyresponsible for neural degeneration and neural death, which causes braindamage or death of the individual. Adenosine A₁ agonists which mimic thecentral inhibitory effects of adenosine may therefore be useful asneuroprotective agents. Adenosine has been proposed as an endogenousanticonvulsant agent, inhibiting glutamate release from excitory neuronsand inhibiting neuronal firing. Adenosine agonists therefore may be usedas antiepileptic agents. Adenosine antagonists stimulate the activity ofthe CNS and have proven to be effective as cognition enhancers.Selective A_(2A)-antagonists have therapeutic potential in the treatmentof various forms of dementia, for example in Alzheimer's disease and areuseful as neuroprotective agents. Adenosine A_(2A)-receptor antagonistsinhibit the release of dopamine from central synaptic terminals andstimulate locomotor activity and consequently improve Parkinsoniansymptoms. The central activities of adenosine are also implicated in themolecular mechanism underlying sedation, hypnosis, schizophrenia,anxiety, pain, respiration, depression and substance abuse. Drugs actingat adenosine receptors therefore have therapeutic potential assedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics,respiratory stimulants and antidepressants, and they may be used in thetreatment of ADHD (attention deficit hyper-activity disorder).

An important role for adenosine in the cardiovascular system is as acardioprotective agent. Levels of endogenous adenosine increase inresponse to ischaemia and hypoxia, and protect cardiac tissue during andafter trauma (preconditioning). Adenosine agonists thus have potentialas cardioprotective agents.

Adenosine modulates many aspects of renal function, including reninrelease, glomerular filtration rate and renal blood flow. Compounds,which antagonise the renal affects of adenosine, have potential as renalprotective agents. Furthermore, adenosine A₃ and/or A_(2B) antagonistsmay be useful in the treatment of asthma and other allergic responsesorand in the treatment of diabetes mellitus and obesity.

SUMMARY

The present invention provides compounds containing the benzothiazolemoiety, prodrugs of compounds containing the benzothiazole moiety,compositions comprising the compounds and prodrugs, and methods of usingthe compounds and prodrugs, including in the treatment and/or preventionof diseases mediated by the adenosine receptor.

The compounds of the invention have activity as adenosine receptorligands. Accordingly, in still another aspect, the present inventionprovides methods of inhibiting the adenosine receptor comprisingcontacting an adenosine receptor with an effective amount of a compoundor composition of the invention effective for inhibition. The methodscan be practiced either in vitro or in vivo, and can be used as atherapeutic approach towards the treatment and/or prevention of diseasesassociated with the adenosine receptor.

In one aspect, the present invention provides compounds containing thebenzothiazoleine moiety, and compositions comprising the compounds. Thecompounds have the general structures of formula I and II shown below:

where R can be H or a progroup, R^(P). The progroup R^(P) is covalentlyattached via a carbamate, a thiocarbamate, a dithiocarbamate, a urea, ora thiourea linkage to oxygen atom. The compounds and compositions can beused in methods for the inhibition of A2a receptor.

Also provided are methods of treating at least one phase of cocainedependence in a patient, in which the at least one phase is selectedfrom acquisition, maintenance, extinction, and relapse. The methodsinclude administering to the patient a therapeutically effective amountof the compound of the invention.

DETAILED DESCRIPTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (1992) “Advanced Organic Chemistry 3^(rd) Ed.” Vols.A and B, Plenum Press, New York. The practice of the present inventionwill employ, unless otherwise indicated, conventional methods of massspectroscopy, protein chemistry, biochemistry, recombinant DNAtechniques and pharmacology, within the skill of the art.

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain alkyl group containing from 1 to 6 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl,t-butyl and the like. Preferred lower alkyl groups are groups with 1-4carbon atoms.

As used herein, the term “lower alkenyl” denotes a unsaturated straight-or branched-chain alkyl group containing from 2 to 6 carbon atoms, forexample, ethylen, propylen, isopropylen, n-butylen, i-butylen,2-butylen, t-butylen and the like. Preferred lower alkyl groups aregroups with 2-4 carbon atoms.

The term “cycloalkyl” denotes a saturated carbocyclic group, containing3-6 carbon atoms.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

“Haloalkyl,” by itself or as part of another substituent, refers to analkyl group as defined herein in which one or more of the hydrogen atomsis replaced with a halo group. The term “haloalkyl” is specificallymeant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up toperhaloalkyls. The halo groups substituting a haloalkyl can be the same,or they can be different. For example, the expression “(C₁-C₂)haloalkyl” includes 1-fluoromethyl, 1-fluoro-2-chloroethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

“Haloalkyloxy,” by itself or as part of another substituent, refers to agroup of the formula —O-haloalkyl, where haloalkyl is as defined herein.

The term “lower alkoxy” denotes a group wherein the alkyl residues areas defined above, and which is attached via an oxygen atom.

The term “five or six membered aromatic or non aromatic heterocycle”denotes the following group: aromatic heterocyclic groups are, forexample pyrrol-1-yl, tetrazolyl, imidazol-1 or 2-yl, pyrazol1-yl,pyridin-1,2,3 or 4-yl, pyrazinyl, pyrimidinyl, pyridazinyl,isothiazolyl, isoxazolyl, thiazolyl, thienyl or furyl; Non aromaticheterocyclic groups are, for example, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,thiomorpholin-1,1-dioxo or thiomorpholin-1-oxo.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (e.g., methyl and ethyl esters, acetate or propionategroups or glycol esters) or alkylated such as benzyl and trityl ethers,as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers(e.g., TMS or TIPPS groups) and allyl ethers.

“Prodrug” refers to a derivative of an active compound (drug) thatundergoes a transformation under the conditions of use, such as withinthe body, to release an active drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. The prodrug and active drug may have the same or differentpharmacologic potency, selectivity or specificity, or a differentpharmacological functionality. Prodrugs are typically obtained bymasking a functional group in the drug believed to be in part requiredfor activity with a progroup (defined below) to form a promoiety or“progroup” which undergoes a transformation, such as cleavage, under thespecified conditions of use to release the functional group, and hencethe active drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it may becatalyzed or induced by another agent, such as by an enzyme, by light,by acid, or by a change of or exposure to a physical or environmentalparameter, such as a change of temperature, or combination thereof. Theagent may be endogenous to the conditions of use, such as an enzymepresent in, or secreted by, the cells to which the prodrug isadministered or the acidic conditions of the stomach, or it may besupplied exogenously.

A wide variety of progroups suitable for masking functional groups inactive compounds to yield prodrugs are well-known in the art. Forexample, a hydroxyl functional group may be masked as a sulfonate, esteror carbonate promoiety, which may be hydrolyzed in vitro to provide thehydroxyl group. An amino functional group may be masked as an amide,imine, phosphinyl, phosphonyl, phosphoryl or sulfenyl promoiety, whichmay be hydrolyzed in vivo to provide the amino group. A carboxyl groupmay be masked as an ester (including silyl esters and thioesters), amideor hydrazide promoiety, which may be hydrolyzed in vivo to provide thecarboxyl group. Other specific examples of suitable progroups and theirrespective promoieties will be apparent to those of skill in the art.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active drug, converts the drug into aprodrug. Progroups are typically attached to the functional group of thedrug via bonds that are cleavable under specified conditions of use.

The term “psychotic” as used herein refers to a psychiatric condition inits broadest sense, including hallucinations, a loss of ego boundaries,a gross impairment in reality testing, impairment with the capacity tomeet ordinary demands of life, delusions, any prominent hallucinations,disorganized speech, or disorganized or catatonic behavior, and thelike.

The term “psychosis” refers to a psychiatric symptom, condition orsyndrome in its broadest sense, and can refer to a symptom associatedwith a general medical condition, a disease state or other condition,such as a side effect of drug abuse (a substance-induced disorder) or asa side effect of a medication. Psychosis includes a mental disorder orcondition causing gross distortion or disorganization of a person'smental capacity, affective response, and capacity to recognize reality,communicate, and relate to others to the degree of interfering with hiscapacity to cope with the ordinary demands of everyday life.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. The term does not denote a particular ageor gender.

As used herein, the terms “treat” or “treatment” are usedinterchangeably and are meant to indicate a postponement of developmentof a disease and/or a reduction in the severity of such symptoms thatwill or are expected to develop, where the disease is associated withthe functioning of a adenosine receptor. The terms further includeameliorating existing symptoms, preventing additional symptoms, andameliorating or preventing the underlying metabolic causes of symptoms.

The compounds of the present invention may be used to inhibit or reducethe activity of A2a receptor. In these contexts, inhibition andreduction of activity of A2a receptor refers to a lower level of themeasured activity relative to a control experiment in which the cells orthe subjects are not treated with the test compound. In particularaspects, the inhibition or reduction in the measured activity is atleast a 10% reduction or inhibition. One of skill in the art willappreciate that reduction or inhibition of the measured activity of atleast 20%, 50%, 75%, 90% or 100%, or any number in between, may bepreferred for particular applications.

The Compounds

As described in the Summary, the instant disclosure providesbenzothiazoleine moiety containing compounds and their prodrugs of, suchas the various benzothiazoleine compounds described in U.S. Pat. Nos.6,521,754 and 7,368,446, EP 1 303 272, EP 1 753 760, and U.S.application Ser. No. 11/930,717 filed Oct. 31, 2007 (US2008/0125419). Inparticular, the compounds are of formula I and/or formula II:

where R can be H or a progroup, R^(P). The progroup R^(P) can becovalently attached via a carbamate, a thiocarbamate, a dithiocarbamate,a urea, or a thiourea linkage to the oxygen atom. The compounds andcompositions can be used in methods for the inhibition of A2a receptor.

The nature of the progroup can vary, and will depend upon, among otherfactors, the desired water solubility of the prodrug, its intended modeof administration and/or its intended mechanism or site of metabolism tothe active benzothiazoleine compound. For example, lipophilic groups canbe used to decrease water solubility and hydrophilic groups can be usedto increase water solubility. In this way, prodrugs specificallytailored for selected modes of administration can be obtained. Theprogroup can also be designed to impart the prodrug with otherproperties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues,targeting-specific transporters, transport into the central nervoussystem (CNS), preventions or minimization of toxicity, etc. Groupscapable of imparting prodrugs with these characteristics are well-known,and are described, for example, in Ettmayer et al. (2004) J. Med. Chem.47: 2393-2404. All of the various groups described in these referencescan be utilized in the prodrugs described herein.

The suitability of any particular progroup for a desired mode ofadministration can be confirmed in biochemical assays. For example, if aprodrug is to be administered by injection into a particular tissue ororgan, and the identities of the various enzyme(s) expressed in thetissue or organ are known, the particular prodrug can be tested formetabolism in biochemical assays with the isolated enzyme(s).Alternatively, the particular prodrug can be tested for metabolism tothe benzothiazoleine compound with tissue and/or organ extracts. Usingtissue and/or organ extracts can be of particular convenience when theidentity(ies) of the enzymes expressed in the target tissues or organsare unknown, or in instances when the isolated enzymes are notconveniently available. Skilled artisans will be able to readily selectprogroups having metabolic properties (such as kinetics) suitable forparticular applications using such in vitro tests. The specific prodrugscould also be tested for suitable metabolism in in vitro animal models.

It has surprisingly been found that the compounds of formula I and IIare adenosine receptor ligands.

The present invention, thus provides for the use of compounds of formulaI and/or II or their pharmaceutically acceptable salts for themanufacture of medicaments for the treatment of diseases, related to theadenosine A2 receptor, their manufacture, medicaments based on acompound in accordance with the invention and their production as wellas the use of compounds of formula I and/or II in the control orprevention of illnesses based on the modulation of the adenosine system,such as Alzheimer's disease, Parkinson's disease, neuroprotection,schizophrenia, anxiety, pain, respiration deficits, depression, asthma,allergic responses, hypoxia, ischaemia, seizure and substance abuse.Furthermore, compounds of the present invention may be useful assedatives, muscle relaxants, antipsychotics, antiepileptics,anticonvulsants and cardiaprotective agents. The most preferredindications in accordance with the present invention are those, whichbase on the A_(2A) receptor antagonistic activity and which includedisorders of the central nervous system, for example the treatment orprevention of certain cognition impairment, sleep disorders, anxietydisorders especially generalized anxiety disorder (GAD), panic disorder,bipolar disorder, also known as manic depression or manic-depressivedisorder, obsessive compulsive disorder (OCD), posttraumatic stressdisorder (PTSD), acute stress disorder, social phobia, simple phobias,pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD),major depressive disorder (MDD), postnatal depression, dysthymia,depression associated with Alzheimer's disease, Parkinson's disease, orpsychosis, neuroprotection and Parkinson's disease as well as ADHD anddiabetes mellitus. The compounds of formula I and/or II can be used forthe treatment or prevention of addiction, such as cocaine addiction,nicotine addiction, cocaine addiction, alcohol and amphetamineaddiction, and other chemical dependencies as well as movement disorderssuch as extrapyramidal syndrome, Tic disorders and restless leg syndrome(RLS).

The compounds of formulas I and II and their pharmaceutically usableaddition salts possess valuable pharmacological properties.Specifically, it has been found that the compounds of the presentinvention can be adenosine receptor ligands and possess a high affinitytowards the adenosine A_(2A) receptor.

Methods of Synthesis

The compounds of the invention comprise benzothiazoleine moiety, asdescribed above. The compounds can be obtained from commercial sources,such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.), or Maybridge (Cornwall, England), or the compounds can besynthesized. The compounds of the present invention, and other relatedcompounds having different substituents identified by any of the methodsdescribed above can be synthesized using techniques and materials knownto those of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 3^(rd) Ed., Vols. A and B (Plenum 1992), andGreen and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2^(nd) Ed. (Wiley1991). Starting materials useful for preparing compounds of theinvention and intermediates thereof are commercially available or can beprepared by well-known synthetic methods (see, e.g., Harrison et al.,“Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley andSons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” BeilsteinInstitute of Organic Chemistry, Frankfurt, Germany; Feiser et al.,“Reagents for Organic Synthesis,” Volumes 1-21, Wiley Interscience;Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991;“Theilheimer's Synthetic Methods of Organic Chemistry,” Volumes 1-45,Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience,1991; Larock “Comprehensive Organic Transformations,” VCH Publishers,1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” 3dEdition, John Wiley & Sons, 1995).

Other methods for synthesis of the compounds described herein and/orstarting materials are either described in the art or will be readilyapparent to the skilled artisan. Alternatives to the reagents and/orprotecting groups may be found in the references provided above and inother compendiums well known to the skilled artisan. Guidance forselecting suitable protecting groups can be found, for example, inGreene & Wuts, “Protective Groups in Organic Synthesis,” WileyInterscience, 1999. Accordingly, the synthetic methods and strategypresented herein are illustrative rather than comprehensive.

All of the compounds were investigated in accordance with the test givenhereinafter.

Human Adenosine A_(2A) Receptor

The human adenosine A_(2A) receptor was recombinantly expressed inchinese hamster ovary (CHO) cells using the semliki forest virusexpression system. Cells were harvested, washed twice by centrifugation,homogenised and again washed by centrifugation. The final washedmembrane pellet was suspended in a Tris (50 mM) buffer containing 120 mMNaCl, 5 mM KCl, 2 mM CaCl₂ and 10 mM MgCl₂ (pH 7.4) (buffer A). The[^(3H)]-SCH-58261 (Dionisotti et al., 1997, Br J Pharmacol 121, 353; 1nM) binding assay was carried out in 96-well plates in the presence of2.5 μg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and0.1 U adenosine deaminase in a final volume of 200 μl of buffer A.Non-specific binding was defined using xanthine amine congener (XAC; 2μM). Compounds were tested at 10 concentrations from 10 μM-0.3 nM. Allassays were conducted in duplicate and repeated at least two times.Assay plates were incubated for 1 hour at room temperature beforecentrifugation and then bound ligand determined using a Packard Topcountscintillation counter. IC₅₀ values were calculated using a non-linearcurve fitting program and Ki values calculated using the Cheng-Prussoffequation.

In accordance with the invention, it has been shown that all of thecompounds of formula I and II have a high affinity toward the A_(2A)receptor.

Uses and Administration

The compounds of formula I, formula II and the pharmaceuticallyacceptable salts of the compounds of formula I and formula Ia can beused as medicaments, e.g. in the form of pharmaceutical preparations.The pharmaceutical preparations can be administered orally, e.g. in theform of tablets, coated tablets, dragees, hard and soft gelatinecapsules, solutions, emulsions or suspensions. The administration can,however, also be effected rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions.

The compounds of formula I and formula Ia can be processed withpharmaceutically inert, inorganic or organic carriers for the productionof pharmaceutical preparations. Lactose, corn starch or derivativesthereof, talc, stearic acids or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragees and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active substance no carriersare, however, usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oil and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula I, formula II or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier are also an object of the present invention, as is a process fortheir production, which comprises bringing one or more compounds offormula I and/or formal II and/or pharmaceutically acceptable acidaddition salts and, if desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

In accordance with the invention compounds of formula I and formula IIas well as their pharmaceutically acceptable salts are useful in thecontrol or prevention of illnesses based on the adenosine receptorantagonistic activity, such as Alzheimer's disease, Parkinson's disease,neuroprotection, schizophrenia, anxiety, pain, respiration deficits,depression, asthma, allergic responses, hypoxia, ischaemia, seizure,substance abuse, sleep disorders and cognition disorders. Furthermore,compounds of the present invention may be useful as sedatives, musclerelaxants, antipsychotics, antiepileptics, anticonvulsants andcardioprotective agents and for the production of correspondingmedicaments.

The most preferred indications in accordance with the present inventionare those, which include disorders of the central nervous system, forexample the treatment or prevention of certain depressive disorders,neuroprotection, Parkinson's disease, sleep disorders, cognitiveimpairment and motor disorders.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of formula I, formula IIor of the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated.

Treatment or Prevention of Substance Abuse

In one aspect of the invention, the compounds of formula I and/or II canbe used for the treatment or prevention of substance abuse, and formodulating withdrawal symptoms. Withdrawal symptoms can arise uponreduction of any of a variety of substances. For example, thediscontinued use of tobacco products, all of which contain nicotine,typically results in the onset of nicotine withdrawal conditions.Individuals often suffer the symptoms of nicotine withdrawal as aconsequence of the discontinued use of tobacco in any form, including,but not limited to smoking of cigarette, cigar, or pipe tobacco, or theoral or intranasal ingestion of tobacco or chewing tobacco. Such oral orintranasal tobacco includes, but is not limited to snuff and chewingtobacco. The cessation of nicotine use or reduction in the amount ofnicotine use, is often followed within 24 hours by symptoms includingdysphoric, depressed mood; light-headedness; insomnia; irritability,frustration or anger; anxiety; nervous tremor; difficulty concentrating;restlessness; decreased heart rate; increased appetite or weight gain;and the craving for tobacco or nicotine. These symptoms often causeclinically significant distress or impairment in social, occupational,or other important areas of functioning. The methods described hereinmay be used to alleviate one or more symptoms attributed to nicotinewithdrawal when such symptoms are not due to a general medical conditionand are not better accounted for by another medical disorder. Thepresent method is also helpful to those who have replaced, or partiallyreplaced, their use of tobacco with the use of nicotine replacementtherapy. Thus, such patients can be assisted to reduce and eveneliminate entirely their dependence on nicotine in all forms.

The discontinuing or reduction in administration of an opioid, typicallyself-administration, through injection or orally, through smoking orintranasal ingestion, often results in the presence of a characteristicopioid withdrawal condition. This withdrawal condition can also beprecipitated by administration of an opioid antagonist such as naloxoneor naltrexone after opioid use. Opioid withdrawal is characterized bysymptoms that are generally opposite to the opioid agonist effects.These withdrawal symptoms may include anxiety; restlessness; muscleaches, often in the back and legs; craving for opioids; irritability andincreased sensitivity to pain; dysphoric mood; nausea or vomiting;lacrimation; rhinorrhoea; papillary dilation; piloerection; sweating;diarrhea; yawning; fever; and insomnia. When dependence is onshort-acting opioids, such as heroin, withdrawal symptoms usually occurwithin 6-24 hours after the last dose, while with longer-acting opioids,such as methadone, symptoms may take 2-4 days to emerge. These symptomsoften cause clinically significant distress or impairment in social,occupational or other important areas of functioning. The methodsdescribed herein can be used to alleviate one or more symptomsattributed to opioid withdrawal when such symptoms are not due to ageneral medical condition and are not better accounted for by anothermedical disorder.

The discontinuing of or reduction in use of ethanol (e.g., ethanolcontaining beverages) results in the onset of ethanol withdrawalconditions. Ethanol withdrawal conditions are characterized by symptomsthat begin when blood concentrations of ethanol decline sharply, within4 to 12 hours after ethanol use has been stopped or reduced. Theseethanol withdrawal symptoms include craving for ethanol; autonomichyperactivity (such as sweating or pulse rate greater than 100); handtremor; insomnia; nausea; vomiting; transient visual, tactile, orauditory hallucinations or illusions; psychomotor agitation; anxiety;and grand mal seizures. These symptoms often cause clinicallysignificant distress or impairment in social, occupational, or otherimportant areas of functioning. The methods described herein may be usedto alleviate one or more symptoms attributed to ethanol withdrawal whensuch symptoms are not due to a general medical condition and are notbetter accounted for by another medical disorder.

Cocaine abuse and dependence can cause cognitive, behavioral, andphysiological symptoms. Symptoms of cocaine abuse and dependence caninclude varying degrees of attention deficit hyperactivity disorder andeuphoria; increased energy, excitement, and sociability; less hunger andfatigue; a marked feeling of physical and mental strength; dysphoria;decreased sensation of pain; and craving for cocaine. Respiratoryeffects include symptoms such as bronchitis, shortness of breath, andchest pain, and cardiovascular effects include symptoms such as heartpalpitations, arrhythmia, cardiomyopathy, and heart attacks. Symptomsalso include dilated pupils, nausea, vomiting, headache, vertigo,anxiety, dizziness, psychosis, and confusion. Administration of cocainethrough snorting or sniffing can result in ear, nose, and throat effectsincluding nasal irritation, nasal crusting, recurrent nosebleeds, nasalstuffiness, and facial pain. In some embodiments, compounds of formula Iand/or formula II treatment reduces at least one symptom of cocaineabuse and dependence in a patient. In some embodiments, nepicstattreatment increases at least one negative subjective symptom of cocaineabuse and dependence.

Cocaine withdrawal symptoms can include a fatigue, lack of pleasure,depression, irritability, sleep disorders, increased appetite,pyschomotor retardation, agitation, extreme suspicion, and craving forcocaine. In some embodiments, compounds of formula I and/or formula IItreatment reduces at least one symptom of cocaine withdrawal.

Substance dependence can be characterized by the phases: acquisition,maintenance, extinction, and relapse. As used herein, the term“acquisition” refers to a phase of substance dependence in whichdependence on the substance is initiated and acquired by a patient. Insome embodiments, compounds of formula I and/or formula II treatmentinhibits the development of the acquisition phase in a patient. In someembodiments, compounds of formula I and/or formula II treatment of theacquisition phase reduces at least one of the amount or frequency ofsubstance use by a patient. In some embodiments, compounds of formula Iand/or formula II treatment of the acquisition phase reduces at leastone DSM-IV symptom of substance abuse and dependence in a patient. Insome embodiments, compounds of formula I and/or formula II treatment ofthe acquisition phase reduces at least one symptom of substance abuseand dependence which include by way of example and without limitation atleast one of euphoria, apathy, irritability, recklessness, poorjudgment, compulsion, aggression, anger, craving for the substance beingabused or depended upon, and mood disorders. In some embodiments,treatment with compounds of formula I and/or formula II reduces thesubstance craving induced by a stressful event in a patient during theacquisition phase.

“Maintenance” refers to a phase of substance dependence in which thereis stable administration to or use of the substance by a patient. Insome embodiments, a 10% variance in at least one of the amount andfrequency of substance use by a patient is considered a stable behavior.In some embodiments, compounds of formula I and/or formula II treatmentof the maintenance phase reduces at least one of the amount andfrequency of substance use by a patient. In some embodiments, compoundsof formula I and/or formula II treatment of the maintenance phasereduces at least one DSM-IV symptom of substance abuse and dependence ina patient. In some embodiments, compounds of formula I and/or formula IItreatment of the maintenance phase reduces at least one symptom ofsubstance abuse and dependence which includes by way of example andwithout limitation at least one of euphoria, apathy, irritability,recklessness, poor judgment, compulsion, aggression, anger, craving forthe substance being abused or depended upon, and mood disorders. In someembodiments, treatment with compounds of formula I and/or formula IIreduces the substance craving induced by a stressful event in a patientduring the maintenance phase.

“Extinction” refers to a phase of substance dependence in which thesubstance is not provided to a patient or a patient abstains from use ofthe substance. In some embodiments, the dependence on the substance isextinguished or reduced in the extinction phase. In some embodiments, atleast one withdrawal symptom occurs in the extinction phase. In someembodiments, compounds of formula I and/or formula II treatment promotesthe development of the extinction phase in a patient. In someembodiments, compounds of formula I and/or formula II treatment of theextinction phase reduces at least one DSM-IV symptom of substance abuseand dependence in a patient. In some embodiments, compounds of formula Iand/or formula II treatment during the extinction phase reduces at leastone symptom of substance abuse and dependence which includes by way ofexample and without limitation at least one of euphoria, apathy,irritability, recklessness, poor judgment, compulsion, aggression,anger, craving for the substance being abused or depended upon, and mooddisorders. In some embodiments, compounds of formula I and/or formula IItreatment reduces the withdrawal symptoms in a patient in the extinctionphase. In some embodiments, treatment with compounds of formula I and/orformula II reduces the substance craving induced by a stressful event ina patient in the extinction phase.

“Relapse” refers to recurrence of at least one symptom of substanceabuse or dependence after a period of abstinence in a patient. In someembodiments, the relapse occurs at the end of remission. In someembodiments, a patient has undergone extinction training prior torelapse. In some embodiments, relapse occurs after drug priming, stress,or exposure to an environment related cue or stimulation that waspreviously associated with substance use. In some embodiments, compoundsof formula I and/or formula II treatment reduces the frequency ofrelapse in a patient. In some embodiments, compounds of formula I and/orformula II treatment of the relapse phase reduces at least one DSM-IVsymptom of substance abuse and dependence in a patient. In someembodiments, compounds of formula I and/or formula II treatment of therelapse phase reduces at least one symptom of substance abuse anddependence which includes by way of example and without limitation atleast one of euphoria, apathy, irritability, recklessness, poorjudgment, compulsion, aggression, anger, craving for the substance beingabused or depended upon, and mood disorders. In some embodiments,compounds of formula I and/or formula II treatment reduces thewithdrawal symptoms in a patient during the relapse phase. In someembodiments, treatment with compounds of formula I and/or formula IIreduces the substance craving induced by a stressful event in a patientduring the relapse phase.

Treatment of substance abuse, dependence, and withdrawal may beconducted in stages. In some embodiments, an initial period ofabstinence from substance use is preferred before induction of treatmentwith compounds of formula I and/or formula II in a patient. In someembodiments, an initial low dose of compounds of formula I and/orformula II is administered to a patient. In some embodiments, the amountof compounds of formula I and/or formula II administered to a patient isescalated until a desired therapeutic response is observed. In someembodiments, the amount of compounds of formula I and/or formula II isescalated in order to determine the optimal dose to treat the conditionwhile minimizing symptoms, side effects, and cravings for the substancein a patient.

In some embodiments, compounds of formula I and/or formula II treatmentpromotes remission. In some embodiments, the dose of compounds offormula I and/or formula II is unchanged or tapered off after remissionis reached in a patient.

Provided are methods of treating a patient suffering from or susceptibleto at least one symptom of abuse of, dependence on, or withdrawal fromat least one substance. The methods include administering to the patienta therapeutically effective amount of compounds of formula I and/orformula II. In some embodiments, the at least one substance is selectedfrom a drug of abuse and a medication. In some embodiments, the drug ofabuse is selected from a psychostimulant agent, an opioid, ahallucinogen, an inhalant, a sedative, a tranquilizer, a hypnotic, ananxiolytic, and an illicit substance. In some embodiments, thepsychostimulant agent is a beta-phenylisopropylamine derivative. In someembodiments, the beta-phenylisopropylamine derivative is selected fromamphetamine, dextroamphetamine, and methamphetamine. In someembodiments, the psychostimulant agent is selected from ecstasy,phenmetrazine, methylphenidate, diethylpropion, pemoline, mazindol, (−)cathione, and fenfluramine. In some embodiments, the opioid is selectedfrom Lortab, Tramadol, heroin, methadone, hydrocodone, and oxycodone. Insome embodiments, the hallucinogen is selected from psilocybin, ahallucinogenic mushroom, lysergic acid diethylamide (LSD), phencyclidine(PCP), and ketamine. In some embodiments, the inhalant is selected frombenzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene,fluorobenzene, o-difluorobenzene, 1,3,5-triflurobenzene,1,2,4-trifluorobenzene, pentafluorotoluene, pentafluorobenzene, andperfluorobenzene. In some embodiments, the medication is selected froman anesthetic, an analgesic, an anticholinergic agent, an antihistamine,a muscle relaxant, a nonsteroidal anti-inflammatory medication, an overthe counter medication, and an antidepressant medication. In someembodiments, the drug of abuse is cocaine, alcohol, caffeine, opium,cannabinoid, cannabis, benzodiazapine carisprodol, tobacco, nicotine,Vicodin, Lorcet, Percocet, Percodan, and Tylox. In some embodiments, thedrug of abuse is cocaine and compounds of formula I and/or formula IIreduces at least one symptom of cocaine abuse and dependence in thepatient selected from attention deficit hyperactivity disorder;euphoria; increased energy, excitement and sociability; less hunger andfatigue; a marked feeling of physical and mental strength; decreasedsensation of pain; bronchitis; shortness of breath; chest pain; heartpalpitations; arrhythmia; cardiomyopathy; heart attack; dilated pupils;nausea; vomiting; headache; vertigo; dizziness; anxiety; pychosis;confusion; nasal irritation; nasal crusting; recurrent nosebleeds; nasalstuffiness; facial pain; dysphoria; and craving for cocaine.

In some embodiments, the drug of abuse is cocaine and compounds offormula I and/or formula II increases at least one negative subjectivesymptom of cocaine abuse and dependence. In some embodiments, the drugof abuse is cocaine and compounds of formula I and/or formula II reducesat least one symptom of cocaine withdrawal selected from fatigue, lackof pleasure, depression, irritability, sleep disorders, increasedappetite, pyschomotor retardation, agitation, extreme suspicion, andcraving for cocaine. In some embodiments, compounds of formula I and/orformula II treatment improves a score of the patient on at least one ofthe attention deficit hyperactivity disorder IV rating scale (ADHD-IV),Hamilton Depression Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), BeckDepression inventory (BDI), apathy scale from NeuropsychiatricInventory, and a cognitive function rating scale. In some embodiments,the cognitive function rating scale is selected from the Wechsler AdultIntelligence Scale-Revised (WAIS-R), Wechsler Memory Scale-Revised(WMS-R), Rey Auditory Verbal Learning Test (RAVLT, Trials I-VII), ReyComplex Figure Test (RCFT), and the Trail Making Test (TMT, Parts A andB).

In some embodiments, compounds of formula I and/or formula II reduces inthe patient at least one of the amount and frequency of substance use bythe patient. In some embodiments, compounds of formula I and/or formulaII reduces in the patient at least one symptom of abuse of, dependenceon, or withdrawal from the at least one substance. In some embodiments,compounds of formula I and/or formula II reduces at least one symptom ofsubstance abuse in the patient selected from recurrent substance useresulting in a failure to fulfill major role obligations at work,school, or home; recurrent substance use in situations in which it isphysically hazardous; recurrent substance-related legal problems; andcontinued substance use despite having persistent or recurrent social orinterpersonal problems caused or exacerbated by the effects of thesubstance. In some embodiments, compounds of formula I and/or formula IIreduces at least one symptom of substance dependence in the patientselected from tolerance; withdrawal; the substance is often taken inlarger amounts or over a longer period then was intended; there is apersistent desire and/or unsuccessful efforts to cut down or controlsubstance use; a great deal of time is spent in at least one ofactivities to obtain the substance, use the substance, and recover fromits effects; at least one of important social, occupational andrecreational activities are given up and/or reduced because of substanceuse; and the substance use is continued despite knowledge of having apersistent and/or recurrent physical and/or psychological problem thatis likely to have been caused or exacerbated by the substance.

In some embodiments, compounds of formula I and/or formula II promotesremission in the patient. In some embodiments, the remission ischaracterized by at least one of early full remission, early partialremission, sustained full remission, and sustained partial remission. Insome embodiments, compounds of formula I and/or formula II prolongs aperiod of remission in the patient. In some embodiments, the methodsfurther include treatment with at least one of contingency managementand cognitive behavioral therapy.

In some embodiments, the methods further include co-administering atherapeutically effective amount of least one other agent selected froma selective serotonin reuptake inhibitor (SSRI), aserotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrinereuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor(NDRI), a serotonin 5-hydroxytryptamine1A (5HT1A) antagonist, a dopamineβ-hydroxylase inhibitor, an adenosine receptor antagonist, an adenosineA2A receptor antagonist, a monoamine oxidase inhibitor (MAOI), amonoamine oxidase B inhibitor, a sodium channel blocker, a calciumchannel blocker, a central and peripheral alpha adrenergic receptorantagonist, a central alpha adrenergic agonist, a central or peripheralbeta adrenergic receptor antagonist, a NK-1 receptor antagonist, acorticotropin releasing factor (CRF) antagonist, an atypicalantidepressant/antipsychotic, a tricyclic, an anticonvulsant, aglutamate antagonist, a gamma-aminobutyric acid (GABA) agonist, a GABAmetabolism enzyme inhibitor, a GABA synthesis activator, a partialdopamine D2 agonist, a dopamine metabolism enzyme inhibitor, acatechol-O-methyl-transferase inhibitor, an opioid receptor antagonist,a mood stabilizer, a direct or indirect dopamine agonist, a partial 5HT1agonist, a serotonin 5HT2 antagonist, an opioid, a carboxylaseinhibitor, a partial opioid agonist, a partial nicotinic agonist, and aninhalant.

In some embodiments, the at least one other agent is a SSRI selectedfrom paroxetine, sertraline, citalopram, escitalopram, and fluoxetine.In some embodiments, the at least one other agent is a SNRI selectedfrom duloxetine, mirtazapine, and venlafaxine. In some embodiments, theat least one other agent is a NRI selected from bupropion andatomoxetine. In some embodiments, the at least other agent is the NDRIbupropion. In some embodiments, the at least one other agent is thedopamine β-hydroxylase inhibitor disulfiram. In some embodiments, the atleast one other agent is the adenosine A2A receptor antagonististradefylline. In some embodiments, the at least one other agent is asodium channel blocker selected from lamotrigine, carbamazepine,oxcarbazepine, and valproate. In some embodiments, the at least oneother agent is a calcium channel blocker selected from nimodopone,lamotrigine, and carbamazepine. In some embodiments, the at least oneother agent is the central and peripheral alpha adrenergic receptorantagonist prazosin. In some embodiments, the at least one other agentis the central alpha adrenergic agonist clonidine. In some embodiments,the at least one other agent is the central or peripheral betaadrenergic receptor antagonist propranolol. In some embodiments, the atleast one other agent is an atypical antidepressant/antipsychoticselected from bupropion, olanzepine, risperidone, and quetiapine. Insome embodiments, the at least one other agent is a tricyclic selectedfrom amitriptyline, amoxapine, desipramine, doxepin, imipramine,nortriptyline, protiptyline, and trimipramine. In some embodiments, theat least one other agent is an anticonvulsant selected from phenytoin,lamotrigine, carbamazepine, oxcarbazepine, valproate, topiramate,tiagabine, vigabatrin, and levetiracetam. In some embodiments, the atleast one other agent is the glutamate antagonist topiramate. In someembodiments, the at least one other agent is a GABA agonist selectedfrom baclofen, valproate, and topiramate. In some embodiments, the atleast one other agent is the dopamine metabolism enzyme inhibitorcarbidopa. In some embodiments, the at least one other agent is thepartial dopamine D2 agonist aripiprazole. In some embodiments, the atleast one other agent is an opioid receptor antagonist selected fromnaltrexone and naloxone. In some embodiments, the at least one otheragent is a mood stabilizer selected from carbamazepine and lithium. Insome embodiments, the at least one other agent is a direct or indirectdopamine agonist selected from dopamine, bromocriptine, pergolide,amantadine, mazindole, and methylphenidate. In some embodiments, the atleast other agent is the partial 5HT1 agonist gepirone. In someembodiments, the at least other agent is the serotonin 5HT2 antagonistritanserin. In some embodiments, the at least other agent is the opioidmethadone. In some embodiments, the at least other agent is the partialopioid agonist buprenorphine. In some embodiments, the at least otheragent is the partial nicotinic agonist champix. In some embodiments, theat least one other agent is an inhalant selected from benzene, toluene,o-xylene, m-xylene, p-xylene, ethylbenzene, fluorobenzene,o-difluorobenzene, 1,3,5-triflurobenzene, 1,2,4-trifluorobenzene,pentafluorotoluene, pentafluorobenzene, and perfluorobenzene. In someembodiments, the methods further include co-administering atherapeutically effective amount of least one other agent selected frombenzodiazepine, levodopa, carisprodol, modafenil, acamprosate,gamma-butyrolactone, gamma-hydroxybutyrate, opium, psilopcybin,hallucinogenic mushroom, tobacco, and nicotine.

In some embodiments, compounds of formula I and/or formula II isadministered to the patient after a period of abstinence from substanceuse by the patient. In some embodiments, the therapeutically effectiveamount of compounds of formula I and/or formula II in the patient isdetermined by escalating the amount of compounds of formula I and/orformula II administered to the patient until a desired therapeuticresponse is observed. In some embodiments, the amount of compounds offormula I and/or formula II is tapered off after remission is reached inthe patient. In some embodiments, the amount of compounds of formula Iand/or formula II is unchanged after remission is reached in thepatient.

Also provided are methods of treating at least one phase of substancedependence on at least one substance in a patient. In some embodiments,the at least one phase of substance dependence is selected fromacquisition, maintenance, extinction, and relapse. The methods includeadministering to the patient a therapeutically effective amount ofcompounds of formula I and/or formula II. In some embodiments, compoundsof formula I and/or formula II inhibits the development of theacquisition phase in the patient. In some embodiments, compounds offormula I and/or formula II promotes the development of the extinctionphase in the patient. In some embodiments, compounds of formula I and/orformula II reduces the frequency of relapse in the patient. In someembodiments, the at least one substance is selected from a drug of abuseand a medication. In some embodiments, the drug of abuse is selectedfrom a psychostimulant agent, an opioid, a hallucinogen, an inhalant, asedative, a tranquilizer, a hypnotic, an anxiolytic, and an illicitsubstance. In some embodiments, the psychostimulant agent is abeta-phenylisopropylamine derivative. In some embodiments, thebeta-phenylisopropylamine derivative is selected from amphetamine,dextroamphetamine, and methamphetamine. In some embodiments, thepsychostimulant agent is selected from ecstasy, phenmetrazine,methylphenidate, diethylpropion, pemoline, mazindol, (−) cathione, andfenfluramine. In some embodiments, the opioid is selected from Lortab,Tramadol, heroin, methadone, hydrocodone, and oxycodone. In someembodiments, the hallucinogen is selected from psilocybin, ahallucinogenic mushroom, lysergic acid diethylamide (LSD), phencyclidine(PCP), and ketamine. In some embodiments, the inhalant is selected frombenzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene,fluorobenzene, o-difluorobenzene, 1,3,5-triflurobenzene,1,2,4-trifluorobenzene, pentafluorotoluene, pentafluorobenzene, andperfluorobenzene. In some embodiments, the medication is selected froman anesthetic, an analgesic, an anticholinergic agent, an antihistamine,a muscle relaxant, a nonsteroidal anti-inflammatory medication, an overthe counter medication, and an antidepressant medication. In someembodiments, the drug of abuse is alcohol, caffeine, opium, cannabinoid,cannabis, benzodiazapine, carisprodol, tobacco, nicotine, Vicodin,Lorcet, Percocet, Percodan, and Tylox.

In some embodiments, compounds of formula I and/or formula II treatmentimproves a score of the patient on at least one of the ADHD-IV, HAM-D,HAM-A, BDI, apathy scale from Neuropsychiatric Inventory, and acognitive function rating scale. In some embodiments, the cognitivefunction rating scale is selected from the WAIS-R, WMS-R, RAVLT, TrialsI-VII, RCFT, and TMT, Parts A and B. In some embodiments, compounds offormula I and/or formula II reduces in the patient at least one of theamount and frequency of use of the at least one substance by thepatient. In some embodiments, compounds of formula I and/or formula IIreduces in the patient at least one symptom of abuse of, dependence on,or withdrawal from the at least one substance. In some embodiments,compounds of formula I and/or formula II reduces at least one symptom ofsubstance abuse in the patient selected from recurrent substance useresulting in a failure to fulfill major role obligations at work,school, or home; recurrent substance use in situations in which it isphysically hazardous; recurrent substance-related legal problems; andcontinued substance use despite having persistent or recurrent social orinterpersonal problems caused or exacerbated by the effects of thesubstance. In some embodiments, compounds of formula I and/or formula IIreduces at least one symptom of substance dependence in the patientselected from tolerance; withdrawal; the substance is often taken inlarger amounts or over a longer period then was intended; there is apersistent desire and/or unsuccessful efforts to cut down or controlsubstance use; a great deal of time is spent in at least one ofactivities to obtain the substance, use the substance, and recover fromits effects; at least one of important social, occupational andrecreational activities are given up and/or reduced because of substanceuse; and the substance use is continued despite knowledge of having apersistent and/or recurrent physical and/or psychological problem thatis likely to have been caused or exacerbated by the substance.

In some embodiments, compounds of formula I and/or formula II promotesremission in the patient. In some embodiments, the remission ischaracterized by at least one of early full remission, early partialremission, sustained full remission, and sustained partial remission. Insome embodiments, compounds of formula I and/or formula II prolongs aperiod of remission in the patient. In some embodiments, the methodsfurther include treatment with at least one of contingency managementand cognitive behavioral therapy.

In some embodiments, the methods further include co-administering atherapeutically effective amount of least one other agent selected froma selective serotonin reuptake inhibitor (SSRI), aserotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrinereuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor(NDRI), a serotonin 5-hydroxytryptamine1A (5HT1A) antagonist, a dopamineβ-hydroxylase inhibitor, an adenosine receptor antagonist, an adenosineA2A receptor antagonist, a monoamine oxidase inhibitor (MAOI), amonoamine oxidase B inhibitor, a sodium channel blocker, a calciumchannel blocker, a central and peripheral alpha adrenergic receptorantagonist, a central alpha adrenergic agonist, a central or peripheralbeta adrenergic receptor antagonist, a NK-1 receptor antagonist, acorticotropin releasing factor (CRF) antagonist, an atypicalantidepressant/antipsychotic, a tricyclic, an anticonvulsant, aglutamate antagonist, a gamma-aminobutyric acid (GABA) agonist, a GABAmetabolism enzyme inhibitor, a GABA synthesis activator, a partialdopamine D2 agonist, a dopamine metabolism enzyme inhibitor, acatechol-O-methyl-transferase inhibitor, an opioid receptor antagonist,a mood stabilizer, a direct or indirect dopamine agonist, a partial 5HT1agonist, a serotonin 5HT2 antagonist, an opioid, a carboxylaseinhibitor, a partial opioid agonist, a partial nicotinic agonist, and aninhalant. In some embodiments, the at least one other agent is a SSRIselected from paroxetine, sertraline, citalopram, escitalopram, andfluoxetine. In some embodiments, the at least one other agent is a SNRIselected from duloxetine, mirtazapine, and venlafaxine. In someembodiments, the at least one other agent is a NRI selected frombupropion and atomoxetine. In some embodiments, the at least other agentis the NDRI bupropion. In some embodiments, the at least one other agentis the dopamine β-hydroxylase inhibitor disulfiram. In some embodiments,the at least one other agent is the adenosine A2A receptor antagonististradefylline. In some embodiments, the at least one other agent is asodium channel blocker selected from lamotrigine, carbamazepine,oxcarbazepine, and valproate. In some embodiments, the at least oneother agent is a calcium channel blocker selected from nimodopone,lamotrigine, and carbamazepine. In some embodiments, the at least oneother agent is the central and peripheral alpha adrenergic receptorantagonist prazosin. In some embodiments, the at least one other agentis the central alpha adrenergic agonist clonidine. In some embodiments,the at least one other agent is the central or peripheral betaadrenergic receptor antagonist propranolol. In some embodiments, the atleast one other agent is an atypical antidepressant/antipsychoticselected from bupropion, olanzepine, risperidone, and quetiapine. Insome embodiments, the at least one other agent is a tricyclic selectedfrom amitriptyline, amoxapine, desipramine, doxepin, imipramine,nortriptyline, protiptyline, and trimipramine. In some embodiments, theat least one other agent is an anticonvulsant selected from phenytoin,lamotrigine, carbamazepine, oxcarbazepine, valproate, topiramate,tiagabine, vigabatrin, and levetiracetam. In some embodiments, the atleast one other agent is the glutamate antagonist topiramate. In someembodiments, the at least one other agent is a GABA agonist selectedfrom baclofen, valproate, and topiramate. In some embodiments, the atleast one other agent is the dopamine metabolism enzyme inhibitorcarbidopa. In some embodiments, the at least one other agent is thepartial dopamine D2 agonist aripiprazole. In some embodiments, the atleast one other agent is an opioid receptor antagonist selected fromnaltrexone and naloxone. In some embodiments, the at least one otheragent is a mood stabilizer selected from carbamazepine and lithium. Insome embodiments, the at least one other agent is a direct or indirectdopamine agonist selected from dopamine, bromocriptine, pergolide,amantadine, mazindole, and methylphenidate. In some embodiments, the atleast other agent is the partial 5HT 1 agonist gepirone. In someembodiments, the at least other agent is the serotonin 5HT2 antagonistritanserin. In some embodiments, the at least other agent is the opioidmethadone. In some embodiments, the at least other agent is the partialopioid agonist buprenorphine. In some embodiments, the at least otheragent is the partial nicotinic agonist champix. In some embodiments, theat least one other agent is an inhalant selected from benzene, toluene,o-xylene, m-xylene, p-xylene, ethylbenzene, fluorobenzene,o-difluorobenzene, 1,3,5-triflurobenzene, 1,2,4-trifluorobenzene,pentafluorotoluene, pentafluorobenzene, and perfluorobenzene. In someembodiments, the methods further include co-administering atherapeutically effective amount of least one other agent selected frombenzodiazepine, levodopa, carisprodol, modafenil, acamprosate,gamma-butyrolactone, gamma-hydroxybutyrate, opium, psilopcybin,hallucinogenic mushroom, tobacco, and nicotine.

In some embodiments, compounds of formula I and/or formula II isadministered to the patient after a period of abstinence from substanceuse by the patient. In some embodiments, the therapeutically effectiveamount of compounds of formula I and/or formula II in the patient isdetermined by escalating the amount of compounds of formula I and/orformula II administered to the patient until a desired therapeuticresponse is observed. In some embodiments, the amount of compounds offormula I and/or formula II is tapered off after remission is reached inthe patient. In some embodiments, the amount of compounds of formula Iand/or formula II is unchanged after remission is reached in thepatient.

Also provided are methods of treating at least one phase of cocainedependence in a patient. In some embodiments, the at least one phase isselected from acquisition, maintenance, extinction, and relapse. Themethods include administering to the patient a therapeutically effectiveamount of compounds of formula I and/or formula II. In some embodiments,compounds of formula I and/or formula II inhibits the development of theacquisition phase in the patient. In some embodiments, compounds offormula I and/or formula II promotes development of the extinction phasein the patient. In some embodiments, compounds of formula I and/orformula II reduces the frequency of relapse in the patient. In someembodiments, compounds of formula I and/or formula II reduces in thepatient at least one symptom of abuse of, dependence on, or withdrawalfrom cocaine. In some embodiments, compounds of formula I and/or formulaII reduces at least one symptom of cocaine abuse in the patient selectedfrom recurrent cocaine use resulting in a failure to fulfill major roleobligations at work, school, or home; recurrent cocaine use insituations in which it is physically hazardous; recurrentcocaine-related legal problems; and continued cocaine use despite havingpersistent or recurrent social or interpersonal problems caused orexacerbated by the effects of the cocaine. In some embodiments,compounds of formula I and/or formula II reduces at least one symptom ofcocaine dependence in the patient selected from tolerance; withdrawal;the cocaine is often taken in larger amounts or over a longer periodthen was intended; there is a persistent desire or unsuccessful effortsto cut down or control cocaine use; a great deal of time is spent inactivities to obtain the cocaine, use the cocaine, or recover from itseffects; important social, occupational or recreational activities aregiven up or reduced because of cocaine use; and the cocaine use iscontinued despite knowledge of having a persistent or recurrent physicalor psychological problem that is likely to have been caused orexacerbated by the cocaine. In some embodiments, compounds of formula Iand/or formula II reduces at least one symptom of cocaine abuse anddependence selected from attention deficit hyperactivity disorder;euphoria; increased energy, excitement and sociability; less hunger andfatigue; a marked feeling of physical and mental strength; decreasedsensation of pain; bronchitis; shortness of breath; chest pain; heartpalpitations; arrhythmia; cardiomyopathy; heart attack; dilated pupils;nausea; vomiting; headache; vertigo; dizziness; anxiety; pychosis;confusion; nasal irritation; nasal crusting; recurrent nosebleeds; nasalstuffiness; facial pain; dysphoria; and craving for cocaine. In someembodiments, compounds of formula I and/or formula II increases at leastone negative subjective symptom of cocaine abuse and dependence. In someembodiments, compounds of formula I and/or formula II reduces at leastone symptom of cocaine withdrawal selected from fatigue, lack ofpleasure, depression, irritability, sleep disorders, increased appetite,pyschomotor retardation, agitation, extreme suspicion, and craving forcocaine. In some embodiments, compounds of formula I and/or formula IIimproves a score of the patient on at least one of ADHD-IV, HAM-D,HAM-A, BDI, apathy scale from Neuropsychiatric Inventory, and acognitive function rating scale. In some embodiments, the cognitivefunction rating scale is selected from WAIS-R, WMS-R, RAVLT, TrialsI-VII, RCFT, and TMT, Parts A and B. In some embodiments, compounds offormula I and/or formula II reduces at least one of the amount andfrequency of cocaine use by the patient. In some embodiments, compoundsof formula I and/or formula II promotes remission in the patient.

In some embodiments, the remission is characterized by at least one ofearly full remission, early partial remission, sustained full remission,and sustained partial remission. In some embodiments, compounds offormula I and/or formula II prolongs a period of remission in thepatient. In some embodiments, the methods further include treatment withat least one of contingency management and cognitive behavioral therapy.

In some embodiments, the methods further include co-administering atherapeutically effective amount of least one other agent selected froma selective serotonin reuptake inhibitor (SSRI), aserotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrinereuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor(NDRI), a serotonin 5-hydroxytryptamine1A (5HT1A) antagonist, a dopamineβ-hydroxylase inhibitor, an adenosine receptor antagonist, an adenosineA2A receptor antagonist, a monoamine oxidase inhibitor (MAOI), amonoamine oxidase B inhibitor, a sodium channel blocker, a calciumchannel blocker, a central and peripheral alpha adrenergic receptorantagonist, a central alpha adrenergic agonist, a central or peripheralbeta adrenergic receptor antagonist, a NK-1 receptor antagonist, acorticotropin releasing factor (CRF) antagonist, an atypicalantidepressant/antipsychotic, a tricyclic, an anticonvulsant, aglutamate antagonist, a gamma-aminobutyric acid (GABA) agonist, a GABAmetabolism enzyme inhibitor, a GABA synthesis activator, a partialdopamine D2 agonist, a dopamine metabolism enzyme inhibitor, acatechol-O-methyl-transferase inhibitor, an opioid receptor antagonist,a mood stabilizer, a direct or indirect dopamine agonist, a partial 5HT1agonist, a serotonin 5HT2 antagonist, an opioid, a carboxylaseinhibitor, a partial opioid agonist, a partial nicotinic agonist, and aninhalant. In some embodiments, the at least one other agent is a SSRIselected from paroxetine, sertraline, citalopram, escitalopram, andfluoxetine. In some embodiments, the at least one other agent is a SNRIselected from duloxetine, mirtazapine, and venlafaxine. In someembodiments, the at least one other agent is a NRI selected frombupropion and atomoxetine. In some embodiments, the at least other agentis the NDRI bupropion. In some embodiments, the at least one other agentis the dopamine β-hydroxylase inhibitor disulfiram. In some embodiments,the at least one other agent is the adenosine A2A receptor antagonististradefylline. In some embodiments, the at least one other agent is asodium channel blocker selected from lamotrigine, carbamazepine,oxcarbazepine, and valproate. In some embodiments, the at least oneother agent is a calcium channel blocker selected from nimodopone,lamotrigine, and carbamazepine. In some embodiments, the at least oneother agent is the central and peripheral alpha adrenergic receptorantagonist prazosin. In some embodiments, the at least one other agentis the central alpha adrenergic agonist clonidine. In some embodiments,the at least one other agent is the central or peripheral betaadrenergic receptor antagonist propranolol. In some embodiments, the atleast one other agent is an atypical antidepressant/antipsychoticselected from bupropion, olanzepine, risperidone, and quetiapine. Insome embodiments, the at least one other agent is a tricyclic selectedfrom amitriptyline, amoxapine, desipramine, doxepin, imipramine,nortriptyline, protiptyline, and trimipramine. In some embodiments, theat least one other agent is an anticonvulsant selected from phenytoin,lamotrigine, carbamazepine, oxcarbazepine, valproate, topiramate,tiagabine, vigabatrin, and levetiracetam. In some embodiments, the atleast one other agent is the glutamate antagonist topiramate. In someembodiments, the at least one other agent is a GABA agonist selectedfrom baclofen, valproate, and topiramate. In some embodiments, the atleast one other agent is the dopamine metabolism enzyme inhibitorcarbidopa. In some embodiments, the at least one other agent is thepartial dopamine D2 agonist aripiprazole. In some embodiments, the atleast one other agent is an opioid receptor antagonist selected fromnaltrexone and naloxone. In some embodiments, the at least one otheragent is a mood stabilizer selected from carbamazepine and lithium. Insome embodiments, the at least one other agent is a direct or indirectdopamine agonist selected from dopamine, bromocriptine, pergolide,amantadine, mazindole, and methylphenidate. In some embodiments, the atleast other agent is the partial 5HT 1 agonist gepirone. In someembodiments, the at least other agent is the serotonin 5HT2 antagonistritanserin. In some embodiments, the at least other agent is the opioidmethadone. In some embodiments, the at least other agent is the partialopioid agonist buprenorphine. In some embodiments, the at least otheragent is the partial nicotinic agonist champix. In some embodiments, theat least one other agent is an inhalant selected from benzene, toluene,o-xylene, m-xylene, p-xylene, ethylbenzene, fluorobenzene,o-difluorobenzene, 1,3,5-triflurobenzene, 1,2,4-trifluorobenzene,pentafluorotoluene, pentafluorobenzene, and perfluorobenzene. In someembodiments, the methods further include co-administering atherapeutically effective amount of least one other agent selected frombenzodiazepine, levodopa, carisprodol, modafenil, acamprosate,gamma-butyrolactone, gamma-hydroxybutyrate, opium, psilopcybin,hallucinogenic mushroom, tobacco, and nicotine. In some embodiments,compounds of formula I and/or formula II is administered to the patientafter a period of abstinence from cocaine use by the patient. In someembodiments, the therapeutically effective amount of compounds offormula I and/or formula II in the patient is determined by escalatingthe amount of compounds of formula I and/or formula II administered tothe patient until a desired therapeutic response is observed. In someembodiments, the amount of compounds of formula I and/or formula II istapered off after remission from cocaine dependence is reached in thepatient. In some embodiments, the amount of compounds of formula Iand/or formula II is unchanged after remission from cocaine dependenceis reached in the patient. In some embodiments, compounds of formula Iand/or formula II treats at least one symptom of abuse of, dependenceon, or withdrawal from at least one secondary substance in the patient.In some embodiments, the at least one secondary substance is selectedfrom a drug of abuse and a medication. In some embodiments, the drug ofabuse is selected from a psychostimulant agent, an opioid, ahallucinogen, an inhalant, a sedative, a tranquilizer, a hypnotic, ananxiolytic, and an illicit substance. In some embodiments, thepsychostimulant agent is a beta-phenylisopropylamine derivative. In someembodiments, the beta-phenylisopropylamine derivative is selected fromamphetamine, dextroamphetamine, and methamphetamine. In someembodiments, the psychostimulant agent is selected from ecstasy,phenmetrazine, methylphenidate, diethylpropion, pemoline, mazindol, (−)cathione, and fenfluramine. In some embodiments, the opioid is selectedfrom Lortab, Tramadol, heroin, methadone, hydrocodone, and oxycodone. Insome embodiments, the hallucinogen is selected from psilocybin, ahallucinogenic mushroom, lysergic acid diethylamide (LSD), phencyclidine(PCP), and ketamine. In some embodiments, the inhalant is selected frombenzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene,fluorobenzene, o-difluorobenzene, 1,3,5-triflurobenzene,1,2,4-trifluorobenzene, pentafluorotoluene, pentafluorobenzene, andperfluorobenzene. In some embodiments, the medication is selected froman anesthetic, an analgesic, an anticholinergic agent, an antihistamine,a muscle relaxant, a nonsteroidal anti-inflammatory medication, an overthe counter medication, and an antidepressant medication. In someembodiments, the drug of abuse is alcohol, caffeine, opium, cannabinoid,cannabis, benzodiazapine, carisprodol, tobacco, nicotine, Vicodin,Lorcet, Percocet, Percodan, and Tylox.

In another aspect of the invention, the methods include administering tothe patient a therapeutically effective amount of compounds of formula Iand/or formula II in combination with behavioral therapy includingcontingency management, cognitive behavioral therapy, motivationalenhancement therapy, referral to self-help groups, and the like, for thetreatment or prevention of drug use.

It will be readily apparent to one of ordinary skill in the relevantarts that other suitable modifications and adaptations to the methodsand applications described herein are suitable and may be made withoutdeparting from the scope of the invention or any embodiment thereof.While the invention has been described in connection with certainembodiments, it is not intended to limit the invention to the particularforms set forth, but on the contrary, it is intended to cover suchalternatives, modifications and equivalents as may be included withinthe spirit and scope of the invention as defined by the followingclaims.

1. A compound of formula I:

wherein R is H or a progroup.